Sting inhibitors and their therapeutic uses

The present invention concerns the use of compounds of formula (I) and their salts, in the form of the mixture of their diastereoisomers or individual diastereoisomer, for inhibiting cancer-related inflammation.

Dinucleotides are bioactive molecules for which a signaling role in mammalian cells has emerged in recent years. In particular, cyclic dinucleotides, such as cyclic GMP-AMP (cGAMP), have been described as activators of the inflammatory response (1). Cellular cGAMP is produced by the cyclic DNA sensor GMP-AMP Synthase (cGAS), following its interaction with immune-stimulatory nucleic acids, including ssDNA, dsDNA and RNA:DNA hybrids. Subsequent interaction of cGAMP with the Stimulator of Interferon Genes (STING, also known as transmembrane protein 173 or TMEM173) triggers a signaling cascade that culminates with the production of pro-inflammatory cytokines and type I interferon (IFN). Consequently, dysregulation of this pathway fuels several inflammatory human pathologies, including autoimmune, auto-inflammatory and malignant disorders (2).

The development of therapeutic means to influence the cGAS-STING signaling pathway is of particular interest, notably in the light of immune-stimulatory nucleic acids arising from non-pathological situations. Indeed, several physiological processes can generate nucleic acid species by-products that, in absence of regulatory mechanisms, elicit inflammatory responses and foster inflammatory pathologies (2).

Likewise, uncontrolled activation of STING leads to chronic inflammation, which is key in many human pathologies such as autoimmune diseases and cancer.

Small molecules that associate with STING to prevent its activation have been identified recently through screening approaches (4, 5) or using in silico modelling (6). However, in certain pathologies, what determines the outcome of STING activation or inhibition remains unknown (7).

Therefore, there is a need for the development of novel and efficient therapies targeting STING, especially focusing on inhibiting STING activation.

Particularly, there is a need for novel and efficient anti-cancer drugs useful for preventing and/or treating cancer-related inflammation.

The present invention proposes compounds of formula (I) which aim to solve these needs:

Indeed, the compounds of the invention, of formula (I), are analogs of diadenosine tetraphosphate (Ap4A).

Diadenosine tetraphosphate (Ap4A) is abundantly produced by the Lysyl-tRNA synthetase (LysRS) upon immunological stress (9, 10). The inventors have now found that Ap4A produced by LysRS suppresses inflammatory responses through inhibition of STING-dependent signaling.

Thus, the compounds of the present invention are able to inhibit STING-dependent signaling, and can be expected to decrease cancer-related inflammation.

Consequently, the present invention relates to a compound chosen from compounds of formula (I), their diastereoisomers and their salts, for use for inhibiting inflammation. Preferably, the present invention relates to a compound chosen from compounds of formula (I), their diastereoisomers and their salts, for use for inhibiting cancer-related inflammation.

Another object of the invention relates to a compound chosen from compounds of formula (II), their diastereoisomers and their salts.

Another object of the invention relates to a composition comprising, in a pharmaceutically acceptable medium, at least one compound of formula (II), one of its diastereoisomers or one of its salts.

Another object of the invention also relates to the use of a compound of formula (II), one of its diastereoisomers or one of its salts as a medicament.

Another object of the invention also relates to the use of a compound of formula (II), one of its diastereoisomers or one of its salts as an anti-inflammatory agent.

According to a first aspect, the present invention relates to a compound chosen from compounds of formula (I), their diastereoisomers and their salts, for use for inhibiting inflammation, especially cancer-related inflammation.

The compounds of formula (I) are the following:

wherein Z is —OH, —OP(S)(OAdo)(OH), N, NH, —CHor

wherein R2 and R3 each represents a C1-C6 alkyl group or an aryl group,

wherein Z represents —OH or —OP(O)(OH),

wherein Z represents —OH, —OP(O)(OH)or —OP(O)(OH)(OAdo),

wherein Z represents a covalent bond, H, —OH or a C1-C6 alkyl group,

wherein Z represents a covalent bond, H, —OH or a C1-C5 alkyl group.

In the last two definitions of R1, when Z is a covalent bond, it means that the cycloalkane is directly linked to Y. Of course, preferably, at least two Z substituents, each representing a covalent bond, so that R1 is linked to each Y to give formula (I).

By “C1-C6 alkyl”, it is meant a linear hydrocarbon group comprising from 1 to 6 carbon atoms, or a branched hydrocarbon group comprising from 3 to 6 carbon atoms. Examples of C1-C6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl and n-hexyl groups, and preferably methyl, n-butyl, n-pentyl, n-hexyl, isopropyl or tert-butyl. More preferably, the C1-C6 alkyl is methyl or isopropyl.

By “C1-C5 alkyl”, it is meant a linear hydrocarbon group comprising from 1 to 5 carbon atoms, or a branched hydrocarbon group comprising from 3 to 5 carbon atoms. Examples of C1-C5 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and isopentyl groups, and preferably methyl, n-butyl, n-pentyl, isopropyl or tert-butyl. More preferably, the C1-C5 alkyl is methyl or isopropyl.

By “aryl”, it is meant a monocyclic or polycyclic aromatic hydrocarbon group, which may be optionally substituted. Preferably, the aryl group is a phenyl. The aryl may be substituted by at least one alkyl group. A preferred example of aryl group is phenyl.

The adenosine residue (Ado) is the residue represented by the following formula (A):

Said residue is linked to the compound of formula (I) on the oxygen (links indicated by stars on the above formula). Thus, said residue is linked to the oxygen of the compound of formula (I) thanks to the carbon 5′ of the ribose residue.

In other words, the compounds of formula (I) are as follows:

By “salt”, it is meant a pharmaceutically acceptable salt. Such salts correspond to any salt of a compound of formula (I) with a base.

By “diastereoisomer”, it is meant a type of stereoisomer. Specifically, diastereoisomers are compounds which are non-mirror image non-identical stereoisomers. The compounds of the invention may be used either as diastereoisomeric mixtures, or as their individual diastereoisomers.

Preferably, the compound is chosen from compounds of formula (I), their diastereoisomers and their salts, wherein:

wherein Z is Nor

wherein R2 and R3 each represents a C1-C6 alkyl group or an aryl group,

wherein Z represents a covalent bond, H, —OH or a C1-C6 alkyl group,

wherein Z represents a covalent bond, H, —OH or a C1-C5 alkyl group.

Alternatively, preferably, the compound is chosen from compounds of formula (I), their diastereoisomers and their salts, wherein:

wherein Z is —OH, —OP(S)(OAdo)(OH) or —CH,

wherein Z represents —OH,

wherein Z represents —OP(O)(OH)or —OP(O)(OH)(OAdo).

Preferably, the compound of formula (I) is such that:

wherein Z is —OH.

Said compound is STAN-1 («STAN» for STING ANtagonist):

Preferably, the compound of formula (I) is such that: